Substituted 5-vinylphenyl-1-phenyl-pyrazole cannabinoid modulators

ABSTRACT

This invention is directed to a cannabinoid modulator compound of formula (I): 
     
       
         
         
             
             
         
       
     
     or a form thereof, and methods for use in treating, ameliorating or preventing a cannabinoid receptor mediated syndrome, disorder or disease.

FIELD OF THE INVENTION

This invention is directed to substituted5-vinylphenyl-1-phenyl-pyrazole cannabinoid (CB) modulator compounds andmethods for use in treating, ameliorating or preventing a cannabinoidreceptor mediated syndrome, disorder or disease.

BACKGROUND OF THE INVENTION

Before the discovery of the cannabinoid CB1 and CB2 receptors, the termcannabinoid was used to describe the biologically active components ofcannabis sativa, the most abundant of which aredelta-9-tetrahydrocannabinol (THC) and cannabidiol.

THC is a moderately potent partial agonist of the CB1 and CB2 receptorsand is considered the “classical cannabinoid,” a term now used to referto other analogues and derivatives that are structurally related to thetricyclic dibenzopyran THC core. The term “nonclassical cannabinoid”refers to cannabinoid agonists structurally related to cannabidiol.

Pharmacological investigations have concentrated on selective CBreceptor modulators of the pyrazole structural class, which include SR141716A (the monohydrochloride salt of SR 141716) and SR 144528.

Pyrazole cannabinoid modulators are one among the many differentstructural classes which have aided the development of CB pharmacology,have helped to determine the biological effects mediated by thecannabinoid receptors, will lead to further refinement of currentcompounds and will be a source of new chemical classes in the future.

Certain compounds (including SR 141716, SR 144528 and the like) thatwere originally classified as selective antagonists are now consideredto act as “inverse agonists” rather than pure antagonists. Inverseagonists have the ability to decrease the constitutive level of receptoractivation in the absence of an agonist instead of only blocking theactivation induced by agonist binding at the receptor. The constitutiveactivity of CB receptors has important implications since there is alevel of continuous signaling by both CB1 and CB2 even in the absence ofan agonist. For example, SR 141716A increases CB1 protein levels andsensitizes cells toward agonist action, thus indicating that inverseagonists may be another class of ligands used to modulate theendocannabinoid system and the downstream signaling pathways activatedby CB receptors.

Advances in the synthesis of CB and cannabimimetic ligands havefurthered the development of receptor pharmacology and provided evidencefor the existence of additional cannabinoid receptor sub-types. However,there remains an ongoing need for the identification and development ofCB1 or CB2 receptor cannabinoid modulators for the treatment of avariety of CB receptor modulated syndromes, disorders and diseases.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of formula (I):

or a form thereof, useful as a cannabinoid receptor modulator, whereinR_(1a), R_(1b), R₂ and R₃ are as defined herein.

The present invention is also directed to a method for use of a compoundof formula (I) in treating, ameliorating or preventing a cannabinoidreceptor mediated syndrome, disorder or disease.

The present invention is further directed to a method for treating,ameliorating or preventing a cannabinoid receptor mediated syndrome,disorder or disease in a patient in need thereof comprisingadministering to the patient an effective amount of a compound offormula (I).

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to a compound having a structure according toformula (I):

or a form thereof, wherein

-   R_(1a) is hydrogen or alkyl;-   R_(1b) is selected from C₃₋₁₂cycloalkyl, heterocyclyl, aryl,    heteroaryl or alkyl, wherein alkyl is optionally substituted with    carboxy, C₃₋₁₂cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein    each instance of C₃₋₁₂cycloalkyl, heterocyclyl, aryl or heteroaryl    is optionally substituted with one, two, three or four substituents    selected from alkyl, alkoxy, cyano, halogen, hydroxy, amino or    alkylamino, and-   wherein heterocyclyl optionally has one nitrogen ring atom attached    to the formula (I) nitrogen atom, wherein said nitrogen ring atom is    optionally further substituted with alkyl to form a quaternary    ammonium salt;-   alternatively, R_(1a) and R_(1b) are taken together with the    nitrogen atom of attachment to form a ring selected from piperidinyl    or piperazinyl; and,-   R₂ and R₃ are each selected from one or two alkyl, alkoxy, cyano or    halogen substituents.

An example of the present invention is a compound of formula (I) or aform thereof, wherein R_(1a) is hydrogen.

An example of the present invention is a compound of formula (I) or aform thereof, wherein R_(1b) is selected from C₃₋₁₂cycloalkyl,heterocyclyl, aryl or alkyl, wherein alkyl is optionally substitutedwith carboxy, C₃₋₁₂cycloalkyl or aryl, wherein each instance ofC₃₋₁₂cycloalkyl or aryl is optionally substituted with one, two, threeor four substituents selected from alkyl, alkoxy, cyano, halogen,hydroxy, amino or alkylamino.

An example of the present invention is a compound of formula (I) or aform thereof, wherein R_(1b) is selected from C₃₋₁₂cycloalkyl,heterocyclyl, aryl or alkyl, wherein alkyl is optionally substitutedwith C₃₋₁₂cycloalkyl or aryl, wherein each instance of C₃₋₁₂cycloalkylis optionally substituted with one, two or three alkyl substituents, andwherein each instance of aryl is optionally substituted with an amino oralkylamino substituent.

An example of the present invention is a compound of formula (I) or aform thereof, wherein R_(1b) is selected from cyclohexyl,bicyclo[2.2.1]heptyl, piperidinyl, morpholinyl, phenyl or alkyl, whereinalkyl is optionally substituted with carboxy, cyclohexyl or phenyl,wherein each instance of cyclohexyl or bicyclo[2.2.1]heptyl isoptionally substituted with one, two or three methyl or ethylsubstituents, and wherein each instance of phenyl is optionallysubstituted with an amino or alkylamino substituent.

An example of the present invention is a compound of formula (I) or aform thereof, wherein R_(1b) is selected from C₃₋₁₂cycloalkyl,heterocyclyl or alkyl, wherein alkyl is optionally substituted withC₃₋₁₂cycloalkyl or aryl, wherein C₃₋₁₂cycloalkyl is optionallysubstituted with three alkyl substituents.

An example of the present invention is a compound of formula (I) or aform thereof, wherein R_(1b) is selected from bicyclo[2.2.1]heptyl,piperidinyl or alkyl, wherein alkyl is optionally substituted withcyclohexyl or phenyl, wherein bicyclo[2.2.1]heptyl is optionallysubstituted with three alkyl substituents.

An example of the present invention is a compound of formula (I) or aform thereof, wherein R_(1b) is piperidinyl having one nitrogen ringatom attached to the formula (I) nitrogen atom, wherein said nitrogenring atom is optionally further substituted with methyl to form aquaternary piperidinium salt.

An example of the present invention is a compound of formula (I) or aform thereof, wherein R₂ and R₃ are one or two substituents selectedfrom fluoro or chloro.

An example of the present invention is a compound of formula (I) or aform thereof, wherein R₂ is two substituents selected from fluoro orchloro.

An example of the present invention is a compound of formula (I) or aform thereof, wherein R₂ is two chloro substituents.

An example of the present invention is a compound of formula (I) or aform thereof, wherein R₃ is one chloro substituent.

An example of the present invention is a compound of formula (I) or aform thereof, wherein

-   R_(1a) is hydrogen;-   R_(1b) is selected from cyclohexyl, bicyclo [2.2.1]heptyl,    piperidinyl, morpholinyl, phenyl or alkyl, wherein alkyl is    optionally substituted with carboxy, cyclohexyl or phenyl, wherein    each instance of cyclohexyl or bicyclo[2.2.1]heptyl is optionally    substituted with one, two or three methyl or ethyl substituents, and    wherein each instance of phenyl is optionally substituted with an    amino or alkylamino substituent, or-   R_(1b) is piperidinyl having one nitrogen ring atom attached to the    formula (I) nitrogen atom, wherein said nitrogen ring atom is    optionally further substituted with methyl to form a quaternary    piperidinium salt;-   R₂ is two substituents selected from fluoro or chloro; and-   R₃ is one chloro substituent.

An example of the present invention is a compound of formula (I) or aform thereof wherein R_(1a) is hydrogen and R_(1b), R₂ and R₃ aredependently selected from:

Cpd R_(1b) R₂ R₃ 1 (1S)-1-cyclohexyl-ethyl 2,4-Cl₂ 4-Cl 2(1S)-1-phenyl-ethyl 2,4-Cl₂ 4-Cl 3 (1R,2S,4R)-1,3,3-trimethyl- 2,4-Cl₂4-Cl bicyclo[2.2.1]hept-2-yl) 4 piperidin-1-yl 2,4-Cl₂ 4-Cl 5morpholin-4-yl 2,4-Cl₂ 4-Cl 6 cyclohexyl 2,4-Cl₂ 4-Cl 72-methyl-cyclohexyl 2,4-Cl₂ 4-Cl 8 (1R)-1-cyclohexyl-ethyl 2,4-Cl₂ 4-Cl9 cyclohexyl-methyl 2,4-Cl₂ 4-Cl 10 phenyl 2,4-Cl₂ 4-Cl 11(1R)-1-phenyl-ethyl 2,4-Cl₂ 4-Cl 12 piperidin-1-yl 2,4-Cl₂ 3-Cl 13morpholin-4-yl 2,4-Cl₂ 3-Cl 14 1-methyl-piperidinium 2,4-Cl₂ 4-Cl 15(C-carboxy-C-phenyl)-methyl 2,4-Cl₂ 3-Cl 16 (1S)-1-cyclohexyl-ethyl2,4-Cl₂ 3-Cl 17 (1S)-1-phenyl-ethyl 2,4-Cl₂ 3-Cl 18(1R)-1-cyclohexyl-ethyl 2,4-Cl₂ 3-Cl 19 (1R)-1-phenyl-ethyl 2,4-Cl₂ 3-Cl20 2-amino-phenyl 2,4-Cl₂ 3-Cl 21 (1S)-1-cyclohexyl-ethyl 2,4-F₂ 4-Cl 22(1S)-1-phenyl-ethyl 2,4-F₂ 4-Cl 23 (1R)-1-phenyl-ethyl 2,4-F₂ 4-Cl 24(1R)-1-cyclohexyl-ethyl 2,4-F₂ 4-Cl 25 piperidin-1-yl 2,4-F₂ 4-Cl 26morpholin-4-yl 2,4-F₂ 4-Cl 27 methyl 2,4-Cl₂ 4-Cl 28 R-but-2-yl 2,4-Cl₂4-Cl 29 S-but-2-yl 2,4-Cl₂ 4-Cl

An example of the present invention is a compound or a form thereofselected from the group consisting of:

An example of the present invention includes a representative compoundor a form thereof selected from the group consisting of:

Cpd Name 15-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-cyclohexyl- ethyl]-amide, 25-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-phenyl-ethyl]-amide, 35-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R,2S,4R)-1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl]-amide, 45-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide, 55-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide, 65-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid cyclohexylamide, 75-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole- 3-carboxylic acid(2-methyl-cyclohexyl)-amide, 85-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-cyclohexyl- ethyl]-amide, 95-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid cyclohexylmethyl-amide, 105-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid phenylamide, 115-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-phenyl- ethyl]-amide, 125-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide, 135-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide, 141-{[5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carbonyl]-amino}-1- methyl-piperidinium,15 {[5-[2-(3-chloro-phenyl)-1-methyl-vinyl]- 1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carbonyl]-amino}-phenyl-acetic acid, 165-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-cyclohexyl- ethyl]-amide,17 5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-phenyl-ethyl]-amide, 185-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-cyclohexyl- ethyl]-amide,19 5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-phenyl- ethyl]-amide, 205-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (2-amino-phenyl)-amide, 215-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-cyclohexyl- ethyl]-amide,22 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-phenyl- ethyl]-amide, 235-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]- amide, 245-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-cyclohexyl-ethyl]- amide,25 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide, 265-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide, 275-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid methylamide, 285-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(R)-sec-butyl]-amide, and 295-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(S)-sec-butyl]-amide.

Another example of the present invention includes a compound or a formthereof selected from the group consisting of:

Cpd Name 15-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-cyclohexyl-ethyl]- amide, 25-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-phenyl-ethyl]-amide, 35-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R,2S,4R)-1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl]-amide, 45-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide, 55-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide, 65-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid cyclohexylamide, 75-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (2-methyl-cyclohexyl)- amide, 85-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-cyclohexyl-ethyl]- amide, 95-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid cyclohexylmethyl-amide, 105-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid phenylamide, 115-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]- amide, 125-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide, 135-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide, 165-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-cyclohexyl-ethyl]- amide,17 5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-phenyl-ethyl]-amide, 185-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-cyclohexyl-ethyl]- amide,19 5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]- amide, 215-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-cyclohexyl-ethyl]- amide,23 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]- amide, 245-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-cyclohexyl-ethyl]- amide,28 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(R)-sec-butyl]-amide, and 295-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(S)-sec-butyl]-amide.

A further example of the present invention includes a compound or a formthereof selected from the group consisting of:

Cpd Name 15-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1- cyclohexyl-ethyl]-amide, 25-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-phenyl-ethyl]-amide, 35-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R,2S,4R)-1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl]-amide, 45-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide, 185-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-cyclohexyl- ethyl]-amide,and 28 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(R)-sec-butyl]-amide.

Definitions

As used herein, the following terms are intended to have the followingdefinitions. The definitions herein may specify that the chemical termhas an indicated formula. The particular formula provided is notintended to limit the scope of the invention, but is provided as anillustration of the term. The scope of the per se definition of the termis intended to include the plurality of variations expected to beincluded by one of ordinary skill in the art.

The term “alkyl” means a saturated branched or straight chain monovalenthydrocarbon radical of up to 10 carbon atoms. Alkyl typically includes,but is not limited to, methyl, ethyl, propyl, isopropyl, n-butyl,t-butyl, pentyl, hexyl, heptyl and the like. When further substituted,substituent variables may be placed on any alkyl carbon atom.

The term “alkenyl” means a partially unsaturated branched or straightchain monovalent hydrocarbon radical of up to 10 carbon atoms having atleast one carbon-carbon double bond, whereby the double bond is derivedby the removal of one hydrogen atom from each of two adjacent carbonatoms. Alkenyl typically includes, but is not limited to, ethenyl(vinyl), propenyl (allyl or 2-propenyl), butenyl and the like. Whenfurther substituted, substituent variables may be placed on any alkylcarbon atom.

The term “alkoxy” means a radical of the formula: —O-alkyl. Alkoxytypically includes, but is not limited to, methoxy, ethoxy, propoxy,butoxy and the like. When further substituted, substituent variables maybe placed on any alkoxy carbon atom.

The term “C₃₋₁₂ cycloalkyl” means a saturated or partially unsaturatedhydrocarbon ring system radical or linking group. The term “C₃₋₁₂cycloalkyl” also includes a C₃₋₈ cycloalkyl, C₃₋₁₀ cycloalkyl, C₅₋₈cycloalkyl, C₅₋₁₂ cycloalkyl or C₉₋₁₂ cycloalkyl ring system radical andthe like such as, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, indanyl,indenyl, 1,2,3,4-tetrahydro-naphthalenyl,5,6,7,8-tetrahydro-naphthalenyl,6,7,8,9-tetrahydro-5H-benzocycloheptenyl,5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl,bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl,bicyclo[3.2.1]octenyl, adamantanyl, octahydro-4,7-methano-1H-indenyl,octahydro-2,5-methano-pentalenyl (also referred to ashexahydro-2,5-methano-pentalenyl) and the like. When furthersubstituted, substituent variables may be placed on any ring carbonatom.

The term “heterocyclyl” means a saturated or partially unsaturated ringsystem radical, wherein at least one ring carbon atom has been replacedwith one or more heteroatoms independently selected from N, O, S, S(O)or SO₂. A heterocyclyl ring system further includes a ring system having1, 2, 3, or 4 carbon atom members replaced by a nitrogen atom.Alternatively, a ring may have 0, 1, 2, or 3 nitrogen atom members and 1oxygen or sulfur atom member. Alternatively, up to two adjacent ringmembers may be heteroatoms, wherein one heteroatom is nitrogen and theother heteroatom is selected from N, S, or O.

Heterocyclyl typically includes, but is not limited to, furyl, thienyl,2H-pyrrole, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, pyrrolyl,1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2-imidazolinyl (alsoreferred to as 4,5-dihydro-1H-imidazolyl), imidazolidinyl,2-pyrazolinyl, pyrazolidinyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, tetrazolidinyl,2H-pyran, 4H-pyran, pyridinyl, piperidinyl, 1,4-dioxanyl, morpholinyl,1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl,piperazinyl, azetidinyl, azepanyl, indolizinyl, indolyl, isoindolyl,3H-indolyl, indolinyl (also referred to as 2,3-dihydro-indolyl),benzo[b]furyl, benzo[b]thienyl, 1H-indazolyl, benzimidazolyl,benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl,cinnolinyl, phthalzinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,pteridinyl, quinuclidinyl, hexahydro-1,4-diazepinyl, 1,3-benzodioxolyl(also known as 1,3-methylenedioxyphenyl or benzo[1,3]dioxolyl),2,3-dihydro-1,4-benzodioxinyl (also known as 1,4-ethylenedioxyphenyl),tetrahydro-furanyl, benzo-dihydro-furanyl, tetrahydro-pyranyl,benzo-tetrahydro-pyranyl, tetrahydro-thienyl, benzo-dihydro-thienyl,5,6,7,8-tetrahydro-4H-cyclohepta(b)thienyl,5,6,7-trihydro-4H-cyclohexa(b)thienyl,5,6-dihydro-4H-cyclopenta(b)thienyl, tetrahydro-pyridazinyl,hexahydro-1,4-diazepinyl, hexahydro-1,4-oxazepanyl,2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-benzofuranyl2-aza-bicyclo[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl,8-aza-bicyclo[3.2.1]octyl, 7-oxa-bicyclo[2.2.1]heptyl and the like.

The term “aryl” means a monovalent, unsaturated aromatic hydrocarbonring system radical. Aryl ring systems include phenyl, naphthalenyl,azulenyl, anthracenyl and the like.

The term “heteroaryl” means a monovalent, unsaturated aromatichydrocarbon ring system radical, wherein at least one ring carbon atomhas been replaced with one or more heteroatoms independently selectedfrom N, O, S, S(O) or SO₂, as defined in heterocyclyl above. Heteroarylring systems include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,indolizinyl, indolyl, azaindolyl, isoindolyl, benzo[b]furanyl,benzo[b]thienyl, indazolyl, azaindazolyl, benzoimidazolyl,benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl,benzotriazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl,cinnolinyl, phthalzinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,pteridinyl and the like.

The term “amino” means a radical of the formula: —NH₂.

The term “alkylamino” means a radical of the formula: —NH-alkyl orN(alkyl)₂.

The term “carboxy” means a radical of the formula: —C(O)—OH.

The term “halogen” means the group chloro, bromo, fluoro or iodo.

The term “substituted” means one or more hydrogen atoms on a coremolecule have been replaced with one or more radicals or linking groups,wherein the linking group, by definition is also further substituted.The ability of a particular radical or linking group to replace ahydrogen atom is optimally expected by one skilled to art to result in achemically stable molecule.

The term “dependently selected” means that the structure variables arespecified in an indicated combination.

In general, IUPAC nomenclature rules are used throughout thisdisclosure.

Pharmaceutical Forms

The term “form” or “isolated form”, in any context herein, means thatcertain compounds of the present invention may exist in various isolatedstates such as, without limitation, a salt, stereoisomer, crystalline,polymorph, amorphous, solvate, hydrate, ester, prodrug or metaboliteform. The present invention encompasses all such compound forms andmixtures thereof, including active compounds in the form of essentiallypure enantiomers, racemic mixtures, pure geometric isomers (such as cisand trans stereoisomers), mixtures of geometric isomers and tautomers.

The compounds of the present invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the“pharmaceutically acceptable salts” of the compounds of this inventionrefer to non-toxic acidic/anionic or basic/cationic salt forms.

Suitable pharmaceutically acceptable salts of the compounds of thisinvention include acid addition salts which may, for example, be formedby mixing a solution of the compound according to the invention with asolution of a pharmaceutically acceptable acid such as hydrochloricacid, sulfuric acid, fumaric acid, maleic acid, succinic acid, aceticacid, benzoic acid, citric acid, tartaric acid, carbonic acid orphosphoric acid.

Furthermore when the compounds of the present invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g. sodium or potassium salts; alkaline earth metalsalts, e.g. calcium or magnesium salts; and salts formed with suitableorganic ligands, e.g. quaternary ammonium salts.

Thus, representative pharmaceutically acceptable salts include thefollowing: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium, camsylate (or camphosulfonate),carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate,fumarate, gluconate, glutamate, hydrabamine, hydrobromine,hydrochloride, iodide, isothionate, lactate, malate, maleate, mandelate,mesylate, nitrate, oleate, pamoate, palmitate, phosphate/diphosphate,salicylate, stearate, sulfate, succinate, tartrate, tosylate.

The present invention includes within its scope prodrugs and metabolitesof the compounds of this invention. In general, such prodrugs andmetabolites will be functional derivatives of the compounds that arereadily convertible in vivo into an active compound.

Thus, in the methods of treatment of the present invention, the term“administering” shall encompass the means for treating, ameliorating orpreventing a syndrome, disorder or disease described herein with acompound specifically disclosed or a compound, or prodrug or metabolitethereof, which would obviously be included within the scope of theinvention albeit not specifically disclosed for certain of the instantcompounds.

The term “prodrug” means a pharmaceutically acceptable form of afunctional derivative of a compound of the invention (or a saltthereof), wherein the prodrug may be: 1) a relatively active precursorwhich converts in vivo to an active prodrug component; 2) a relativelyinactive precursor which converts in vivo to an active prodrugcomponent; or 3) a relatively less active component of the compound thatcontributes to therapeutic biological activity after becoming availablein vivo (i.e., as a metabolite). Conventional procedures for theselection and preparation of suitable prodrug derivatives are describedin, for example, “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

The term “metabolite” means a pharmaceutically acceptable form of ametabolic derivative of a compound of the invention(or a salt thereof),wherein the derivative is a relatively less active component of thecompound that contributes to therapeutic biological activity afterbecoming available in vivo.

The present invention contemplates compounds of various isomers andmixtures thereof. The term “isomer” refers to compounds that have thesame composition and molecular weight but differ in a physical orchemical property, or both. Such substances have the same number andkind of atoms but differ in structure. The structural difference may bein constitution (geometric isomers) or in an ability to rotate the planeof polarized light (stereoisomers).

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are stereoisomers wherein an asymmetrically substitutedcarbon atom acts as a chiral center.

The term “chiral” refers to a molecule that is not superposable on itsmirror image, implying the absence of an axis and a plane or center ofsymmetry. The term “enantiomer” refers to one of a pair of molecularspecies that are mirror images of each other and are not superposable.The term “diastereomer” refers to stereoisomers that are not related asmirror images. The symbols “R” and “S” represent the configuration ofsubstituents around a chiral carbon atom(s). The symbols “R*” and “S*”denote the relative configurations of substituents around a chiralcarbon atom(s). .

The term “racemate” or “racemic mixture” refers to a compound ofequimolar quantities of two enantiomeric species, wherein the compoundis devoid of optical activity. The term “optical activity” refers to thedegree to which a chiral molecule or nonracemic mixture of chiralmolecules rotates the plane of polarized light.

The term “geometric isomer” means isomers that differ in the orientationof substituent atoms in relationship to a carbon-carbon double bond, toa cycloalkyl ring, or to a bridged bicyclic system.

Substituent atoms (other than hydrogen) on each side of a carbon-carbondouble bond may be in an E or Z configuration according to theCahn-Ingold-Prelog system sequence rules that rank the two substituentgroups at each carbon atom. In the “E” configuration, the two higherranking substituents are on opposite sides in relationship to thecarbon-carbon double bond. In the “Z” configuration, the two higherranking substituents are oriented on the same side in relationship tothe carbon-carbon double bond.

The isomeric descriptors (“R,” “S” “E,” and “Z”) indicate atomconfigurations relative to a core molecule and are intended to be usedas defined in the literature.

The compounds of the invention may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include combining the free base (orfree acid) of each isomer of an isomeric pair using an optically activeacid (or base) to form an optically active salt (followed by fractionalcrystallization and regeneration of the free base), forming an ester oramide of each of the isomers of an isomeric pair by reaction with anappropriate chiral auxiliary (followed by fractional crystallization orchromatographic separation and removal of the chiral auxiliary), orseparating an isomeric mixture of either an intermediate or a finalproduct using various well known chromatographic methods.

Furthermore, compounds of the present invention may have one or morepolymorph or amorphous crystalline forms and as such are intended to beincluded in the scope of the invention. In addition, some of thecompounds may form solvates with water (i.e., hydrates) or commonorganic solvents (e.g., organic esters such as ethanolate and the like),and such are also intended to be encompassed within the scope of thisinvention.

During any of the processes for preparation of the compounds of thepresent invention, protection of sensitive or reactive groups on any ofthe molecules concerned may be necessary or desirable, or both. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown in the art.

Therapeutic Use

CB1 and CB2 cannabinoid receptors belong to the G-protein-coupledreceptor (GCPR) family, a receptor super-family with a distinctivepattern of seven transmembrane domains, which inhibits N-type calciumchannels and/or adenylate cyclase to inhibit Q-type calcium channels.CB1 receptors are present in the CNS, predominately expressed in brainregions associated with memory and movement such as the hippocampus(memory storage), cerebellum (coordination of motor function, postureand balance), basal ganglia (movement control), hypothalamus (thermalregulation, neuroendocrine release, appetite), spinal cord(nociception), cerebral cortex (emesis) and periphery regions such aslymphoid organs (cell mediated and innate immunity), vascular smoothmuscle cells (blood pressure), gastrointestinal tract (innateantiinflammatory in the tract and in the esophagus, duodenum, jejunum,ileum and colon, controlling esophageal and gastrointestinal motility),lung smooth muscle cells (bronchodilation), eye ciliary body(intraocular pressure).

CB2 receptors appear to be primarily expressed peripherally in lymphoidtissue (cell mediated and innate immunity), peripheral nerve terminals(peripheral nervous system), spleen immune cells (immune systemmodulation) and retina (intraocular pressure). CB2 mRNA is found in theCNS in cerebellar granule cells (coordinating motor function).Pharmacological and physiological evidence also suggests that there maybe other cannabinoid receptor subtypes that have yet to be cloned andcharacterized.

Where activation or inhibition of a CB receptor appears to mediatevarious syndromes, disorders or diseases, potential areas of clinicalapplication include, but are not limited to, controlling appetite,regulating metabolism, diabetes, reducing glaucoma-associatedintraocular pressure, treating social and mood disorders, treatingseizure-related disorders, treating substance abuse disorders, enhancinglearning, cognition and memory, controlling organ contraction and musclespasm, treating bowel disorders, treating respiratory disorders,treating locomotor activity or movement disorders, treating immune andinflammation disorders, regulating cell growth, use in pain management,use as a neuroprotective agent and the like or any combination thereof.

Thus, cannabinoid receptor modulators, including the compounds of theformula (I) of the present invention, are useful for treating,ameliorating or preventing a cannabinoid receptor mediated syndrome,disorder or disease including, but not limited to, controlling appetite,regulating metabolism, diabetes, glaucoma-associated intraocularpressure, pain, social and mood disorders, seizure-related disorders,substance abuse disorders, learning, cognition disorders, memorydisorders, bowel disorders, respiratory disorders, locomotor activitydisorders, movement disorders, immune disorders or inflammationdisorders, controlling organ contraction and muscle spasm, enhancinglearning, enhancing cognition, enhancing memory, regulating cell growth,providing neuroprotection and the like or any combination thereof.

The present invention is directed to a method for treating, amelioratingor preventing a cannabinoid receptor mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a compound offormula (I) or form thereof.

The present invention is directed to a method for treating, amelioratingor preventing a cannabinoid receptor mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject a combination product comprising aneffective amount of a compound of formula (I) and a therapeutic agent.

Therapeutic agents contemplated for use in a combination product of thepresent invention include an anticonvulsant or a contraceptive agent.The anticonvulsant agents include, and are not limited to, topiramate,analogs of topiramate, carbamazepine, valproic acid, lamotrigine,gabapentin, phenytoin and the like and mixtures or pharmaceuticallyacceptable salts thereof The contraceptive agents include, and are notlimited to, such as progestin-only contraceptives and contraceptivesthat include both a progestin component and an estrogen component. Theinvention further includes a pharmaceutical composition wherein thecontraceptive is an oral contraceptive, and wherein the contraceptiveoptionally includes a folic acid component.

The invention also includes a method of contraception in a subjectcomprising the step of administering to the subject a composition,wherein the composition comprises a contraceptive and a CB1 receptorinverse-agonist or antagonist compound of formula (I), wherein thecomposition either reduces the urge to smoke in the subject or assiststhe subject in losing weight, or both.

The present invention includes cannabinoid receptor modulators usefulfor treating, ameliorating or preventing a CB receptor mediatedsyndrome, disorder or disease. The usefulness of a compound of thepresent invention or composition thereof as a CB modulator can bedetermined according to the methods disclosed herein. The scope of suchuse includes treating, ameliorating or preventing a plurality of CBreceptor mediated syndromes, disorders or diseases.

The present invention is also directed to a method for treating,ameliorating or preventing a CB receptor mediated syndrome, disorder ordisease in a subject in need thereof wherein the syndrome, disorder ordisease is related to appetite, metabolism, diabetes,glaucoma-associated intraocular pressure, social and mood disorders,seizures, substance abuse, learning, cognition or memory, organcontraction or muscle spasm, bowel disorders, respiratory disorders,locomotor activity or movement disorders, immune and inflammationdisorders, unregulated cell growth, pain management, neuroprotection andthe like.

A compound of formula (I) for use as a CB receptor modulator includes acompound having a mean inhibition constant (IC₅₀) for CB receptorbinding activity of between about 50 μM to about 0.01 nM; between about25 μM to about 0.01 nM; between about 15 μM to about 0.01 nM; betweenabout 10 μM to about 0.01 nM; between about 1 μM to about 0.01 nM;between about 800 nM to about 0.01 nM; between about 200 nM to about0.01 nM; between about 100 nM to about 0.01 nM; between about 80 nM toabout 0.01 nM; between about 20 nM to about 0.01 nM; between about 10 nMto about 0.1 nM; or about 0.1 nM.

A compound of formula (I) for use as a CB receptor modulator of theinvention includes a compound having a CB1 agonist IC₅₀ for CB1 agonistbinding activity of between about 50 μM to about 0.01 nM; between about25 μM to about 0.01 nM; between about 15 μM to about 0.01 nM; betweenabout 10 μM to about 0.01 nM; between about 1 μM to about 0.01 nM;between about 800 nM to about 0.01 nM; between about 200 nM to about0.01 nM; between about 100 nM to about 0.01 nM; between about 80 nM toabout 0.01 nM; between about 20 nM to about 0.01 nM; between about 10 nMto about 0.1 nM; or about 0.1 nM.

A compound of formula (I) for use as a CB receptor modulator of theinvention includes a compound having a CB1 antagonist IC₅₀ for CB1antagonist binding activity of between about 50 μM to about 0.01 nM;between about 25 μM to about 0.01 nM; between about 15 μM to about 0.01nM; between about 10 μM to about 0.01 nM; between about 1 μM to about0.01 nM; between about 800 nM to about 0.01 nM; between about 200 nM toabout 0.01 nM; between about 100 nM to about 0.01 nM; between about 80nM to about 0.01 nM; between about 20 nM to about 0.01 nM; between about10 nM to about 0.1 nM; or about 0.1 nM.

A compound of formula (I) for use as a CB receptor modulator of theinvention includes a compound having a CB1 inverse-agonist IC₅₀ for CB1inverse-agonist binding activity of between about 50 μM to about 0.01nM; between about 25 μM to about 0.01 nM; between about 15 μM to about0.01 nM; between about 10 μM to about 0.01 nM; between about 1 μM toabout 0.01 nM; between about 800 nM to about 0.01 nM; between about 200nM to about 0.01 nM; between about 100 nM to about 0.01 nM; betweenabout 80 nM to about 0.01 nM; between about 20 nM to about 0.01 nM;between about 10 nM to about 0.1 nM; or about 0.1 nM.

A compound of formula (I) for use as a CB receptor modulator of theinvention includes a compound having a CB2 agonist IC₅₀ for CB2 agonistbinding activity of between about 50 μM to about 0.01 nM; between about25 μM to about 0.01 nM; between about 15 μM to about 0.01 nM; betweenabout 10 μM to about 0.01 nM; between about 1 μM to about 0.01 nM;between about 800 nM to about 0.01 nM; between about 200 nM to about0.01 nM; between about 100 nM to about 0.01 nM; between about 80 nM toabout 0.01 nM; between about 20 nM to about 0.01 nM; between about 10 nMto about 0.1 nM; or about 0.1 nM.

A compound of formula (I) for use as a CB receptor modulator of theinvention includes a compound having a CB2 antagonist IC₅₀ for CB2antagonist binding activity of between about 50 μM to about 0.01 nM;between about 25 μM to about 0.01 nM; between about 15 μM to about 0.01nM; between about 10 μM to about 0.01 nM; between about 1 μM to about0.01 nM; between about 800 nM to about 0.01 nM; between about 200 nM toabout 0.01 nM; between about 100 nM to about 0.01 nM; between about 80nM to about 0.01 nM; between about 20 nM to about 0.01 nM; between about10 nM to about 0.1 nM; or about 0.1 nM.

A compound of formula (I) for use as a CB receptor modulator of theinvention includes a compound having a CB2 inverse-agonist IC₅₀ for CB2inverse-agonist binding activity of between about 50 μM to about 0.01nM; between about 25 μM to about 0.01 nM; between about 15 μM to about0.01 nM; between about 10 μM to about 0.01 nM; between about 1 μM toabout 0.01 nM; between about 800 nM to about 0.01 nM; between about 200nM to about 0.01 nM; between about 100 nM to about 0.01 nM; betweenabout 80 nM to about 0.01 nM; between about 20 nM to about 0.01 nM;between about 10 nM to about 0.1 nM; or about 0.1 nM.

The term “cannabinoid receptor” refers to any one of the known orheretofore unknown subtypes of the class of cannabinoid receptors thatmay be bound by a cannabinoid modulator compound of the presentinvention; in particular, a cannabinoid receptor selected from the groupconsisting of a CB1 receptor and a CB2 receptor. The term “modulator”further refers to the use of a compound of the invention as a CBreceptor agonist, antagonist or inverse-agonist.

The present invention includes a method for treating, ameliorating orpreventing a CB receptor mediated syndrome, disorder or disease in asubject in need thereof comprising the step of administering to thesubject an effective amount of a compound of the present invention orcomposition thereof, wherein the cannabinoid receptor is a CB1 or CB2receptor; and, the compound is an agonist, antagonist or inverse-agonistof the receptor.

The present invention includes a method for treating, ameliorating orpreventing a CB receptor mediated syndrome, disorder or disease in asubject in need thereof comprising the step of administering to thesubject an effective amount of a compound of the present invention in acombination product with a therapeutic agent such as an anticonvulsantor contraceptive agent or composition thereof, wherein the cannabinoidreceptor is a CB1 or CB2 receptor; and, the compound is an agonist,antagonist or inverse-agonist of the receptor.

It should be understood that contraceptive agents suitable for use in acombination product are not limited to oral contraceptives, but alsoinclude other commonly available contraceptives such as those that areadministered transdermally, by injection or via implant.

Except as further specified, “combination product” means apharmaceutical composition comprising a compound of formula (I) incombination with one or more therapeutic agents. The dosages of thecompound of formula (I) and the one or more therapeutic agents areadjusted when combined to achieve an effective amount.

The term “subject” as used herein, refers to a patient, which may be ananimal, or a mammal or a human, which has been the object of treatment,observation or experiment and is at risk of (or susceptible to)developing a CB receptor mediated syndrome, disorder or disease.

The term “administering” is to be interpreted in accordance with themethods of the present invention. Such methods include therapeuticallyor prophylactically administering an effective amount of a compositionor medicament of the present invention at different times during thecourse of a therapy or concurrently as a product in a combination form.

The term “medicament” refers to the use of a compound of formula (I) inthe manufacture of a product for treating, ameliorating or preventing aCB receptor mediated syndrome, disorder or disease.

Prophylactic administration can occur prior to the manifestation ofsymptoms characteristic of a CB receptor mediated syndrome, disorder ordisease such that the syndrome, disorder or disease is treated,ameliorated, prevented or otherwise delayed in its progression. Themethods of the present invention are further to be understood asembracing all therapeutic or prophylactic treatment regimens used bythose skilled in the art.

The term “effective amount” refers to that amount of active compound orpharmaceutical agent that elicits the biological or medicinal responsein a tissue system, animal or human, that is being sought by aresearcher, veterinarian, medical doctor, or other clinician, whichincludes alleviation of the symptoms of the syndrome, disorder ordisease being treated.

The effective amount of an instant compound of the invention is fromabout 0.001 mg/kg/day to about 300 mg/kg/day.

Wherein the present invention is directed to the administration of acombination of a compound of formula (I) and an anticonvulsant orcontraceptive agent, the term “effective amount” means that amount ofthe combination of agents taken together so that the combined effectelicits the desired biological or medicinal response.

As those skilled in the art will appreciate, the effective amounts ofthe components comprising the combination product may be independentlyoptimized and combined to achieve a synergistic result whereby thepathology is reduced more than it would be if the components of thecombination product were used alone.

For example, the effective amount of a combination product comprisingadministration of a compound of formula (I) and topiramate would be theamount of the compound of formula (I) and the amount of topiramate thatwhen taken together or sequentially have a combined effect that iseffective. Further, it will be recognized by one skilled in the art thatin the case of combination product with an effective amount, as in theexample above, the amount of either or both the compound of formula (I)or the anticonvulsant (e.g., topiramate) individually may or may not beeffective.

Wherein the present invention is directed to the administration of acombination product, the instant compound and the anticonvulsant orcontraceptive agent may be co-administered by any suitable means,simultaneously, sequentially or in a single pharmaceutical composition.Where the instant compound(s) and the anticonvulsant or contraceptiveagent components are administered separately, the number of dosages ofeach compound(s) given per day, may not necessarily be the same, e.g.where one compound may have a greater duration of activity, and willtherefore, be administered less frequently.

The compound(s) of formula (I) and the anticonvulsant(s) orcontraceptive agent(s) may be administered via the same or differentroutes of administration. The compound(s) of formula (I) and theanticonvulsant(s) or contraceptive agent(s) may be administered via thesame or different routes of administration.

Suitable examples of methods of administration are orally, intravenous(iv), intramuscular (im), and subcutaneous (sc). Compounds may also beadministrated directly to the nervous system including, but not limitedto the intracerebral, intraventricular, intracerebroventricular,intrathecal, intracisternal, intraspinal or peri-spinal routes and thelike or any combination thereof, or by delivery via intracranial orintravertebral needles and/or catheters with or without pump devices andthe like or any combination thereof.

The compound(s) of formula (I) and the anticonvulsant(s) orcontraceptive agent(s) may be administered according to simultaneous oralternating regimens, at the same or different times during the courseof the therapy, concurrently in divided or single forms.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation and theadvancement of the disease condition. In addition, factors associatedwith the particular patient being treated, including patient's sex, age,weight, diet, time of administration and concomitant diseases, willresult in the need to adjust dosages.

The term “CB receptor mediated syndrome, disorder, or disease” refers tosyndromes, disorders or diseases associated with a biological responsemediated by a CB receptor such that there is discomfort or decreasedlife expectancy to the organism.

CB receptor mediated syndromes, disorders or diseases can occur in bothanimals and humans and include appetite, metabolism, diabetes, obesity,glaucoma-associated intraocular pressure, social, mood, seizure,substance abuse, learning, cognition, memory, organ contraction, musclespasm, bowel, respiratory, locomotor activity, movement, immune,inflammation, cell growth, pain or neurodegenerative related syndromes,disorders or diseases.

Appetite related syndromes, disorders or diseases include obesity,overweight condition, anorexia, bulimia, cachexia, dysregulated appetiteand the like.

Obesity related syndromes, disorders or diseases include obesity as aresult of genetics, diet, food intake volume, metabolic syndrome,disorder or disease, hypothalmic disorder or disease, age, reducedactivity, abnormal adipose mass distribution, abnormal adiposecompartment distribution and the like.

Metabolism related syndromes, disorders or diseases include metabolicsyndrome, dyslipidemia, elevated blood pressure, diabetes, insulinsensitivity or resistance, hyperinsulinemia, hypercholesterolemia,hyperlipidemias, hypertriglyceridemias, atherosclerosis, hepatomegaly,steatosis, abnormal alanine aminotransferase levels, inflammation,atherosclerosis and the like.

Diabetes related syndromes, disorders or diseases include glucosedysregulation, insulin resistance, glucose intolerance,hyperinsulinemia, dyslipidemia, hypertension, obesity and the like.

Type II diabetes mellitus (non-insulin-dependent diabetes mellitus) is ametabolic disorder (i.e., a metabolism related syndrome, disorder ordisease) in which glucose dysregulation and insulin resistance resultsin chronic, long-term medical complications for both adolescents andadults affecting the eyes, kidneys, nerves and blood vessels and canlead to blindness, end-stage renal disease, myocardial infarction orlimb amputation and the like. Glucose dysregulation includes theinability to make sufficient insulin (abnormal insulin secretion) andthe inability to effectively use insulin (resistance to insulin actionin target organs and tissues). Individuals suffering from Type IIdiabetes mellitus have a relative insulin deficiency. That is, in suchindividuals, plasma insulin levels are normal to high in absolute terms,although they are lower than predicted for the level of plasma glucosethat is present.

Type II diabetes mellitus is characterized by the following clinicalsigns or symptoms: persistently elevated plasma glucose concentration orhyperglycemia; polyuria; polydipsia and/or polyphagia; chronicmicrovascular complications such as retinopathy, nephropathy andneuropathy; and macrovascular complications such as hyperlipidemia andhypertension. These micro-and macro-vascular complications can lead toblindness, end-stage renal disease, limb amputation and myocardialinfarction.

Insulin Resistance Syndrome (IRS) (also referred to as Syndrome X,Metabolic Syndrome or Metabolic Syndrome X) is a disorder that presentsrisk factors for the development of Type II diabetes and cardiovasculardisease including glucose intolerance, hyperinsulinemia, insulinresistance, dyslipidemia (e.g. high triglycerides, low HDL-cholesteroland the like), hypertension and obesity.

Social or mood related syndromes, disorders or diseases includedepression, anxiety, psychosis, social affective disorders or cognitivedisorders and the like.

Substance abuse related syndromes, disorders or diseases include drugabuse, drug withdrawal, alcohol abuse, alcohol withdrawal, nicotinewithdrawal, cocaine abuse, cocaine withdrawal, heroin abuse, heroinwithdrawal and the like.

Learning, cognition or memory related syndromes, disorders or diseasesinclude memory loss or impairment as a result of age, disease, sideeffects of medications (adverse events) and the like.

Muscle spasm syndromes, disorders or diseases include multiplesclerosis, cerebral palsy and the like.

Locomotor activity and movement syndromes, disorders or diseases includestroke, Parkinson's disease, multiple sclerosis, epilepsy and the like.

Bowel related syndromes, disorders or diseases include bowel dysmotilityassociated disorders (either accompanied by pain, diarrhea orconstipation or without), irritable bowel syndrome (and other forms ofbowel dysmotility and the like), inflammatory bowel diseases (such asulcerative colitis, Crohn's disease and the like) and celiac disease.

Respiratory related syndromes, disorders or diseases include chronicpulmonary obstructive disorder, emphysema, asthma, bronchitis and thelike.

Immune or inflammation related syndromes, disorders or diseases includeallergy, rheumatoid arthritis, dermatitis, autoimmune disease,immunodeficiency, chronic neuropathic pain and the like.

Cell growth related syndromes, disorders or diseases includedysregulated mammalian cell proliferation, breast cancer cellproliferation, prostrate cancer cell proliferation and the like.

Pain related syndromes, disorders or diseases include central andperipheral pathway mediated pain, bone and joint pain, migraine headacheassociated pain, cancer pain, menstrual cramps, labor pain and the like.

Neurodegenerative related syndromes, disorders or diseases includeParkinson's Disease, multiple sclerosis, epilepsy, ischemia or secondarybiochemical injury collateral to traumatic head or brain injury, braininflammation, eye injury or stroke and the like.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a cannabinoidagonist compound of the present invention or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a cannabinoidagonist compound of the present invention in a combination product withan anticonvulsant or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor inverse-agonist mediated syndrome,disorder or disease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a cannabinoidinverse-agonist compound of the present invention or compositionthereof.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor inverse-agonist mediated syndrome,disorder or disease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a cannabinoidinverse-agonist compound of the present invention in a combinationproduct with an anticonvulsant or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor inverse-agonist mediated syndrome,disorder or disease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a cannabinoidinverse-agonist compound of the present invention in a combinationproduct with one or more contraceptives or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor antagonist mediated syndrome, disorderor disease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a cannabinoidantagonist compound of the present invention or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor antagonist mediated syndrome, disorderor disease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a cannabinoidantagonist compound of the present invention in a combination productwith an anticonvulsant or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor antagonist mediated syndrome, disorderor disease in a subject in need thereof comprising the step ofadministering to the subject a therapeutically or prophylacticallyeffective amount of a cannabinoid antagonist compound of the presentinvention in a combination product with one or more contraceptives orcomposition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor agonist mediated syndrome, disorder or diseasein a subject in need thereof comprising the step of administering to thesubject an effective amount of a CB1 agonist compound of the presentinvention or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor agonist mediated syndrome, disorder or diseasein a subject in need thereof comprising the step of administering to thesubject an effective amount of a CB1 agonist compound of the presentinvention in a combination product with an anticonvulsant or compositionthereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor inverse-agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB1inverse-agonist compound of the present invention or compositionthereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor inverse-agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB1inverse-agonist compound of the present invention in a combinationproduct with an anticonvulsant or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor inverse-agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB1inverse-agonist compound of the present invention in a combinationproduct with one or more contraceptives or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor inverse-agonist mediated appetite relatedobesity related or metabolism related syndrome, disorder or disease in asubject in need thereof comprising the step of administering to thesubject an effective amount of a CB1 inverse-agonist compound of thepresent invention or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor inverse-agonist mediated appetite relatedobesity related or metabolism related syndrome, disorder or disease in asubject in need thereof comprising the step of administering to thesubject an effective amount of a CB1 inverse-agonist compound of thepresent invention in a combination product with an anticonvulsant orcomposition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor inverse-agonist mediated appetite relatedobesity related or metabolism related syndrome, disorder or disease in asubject in need thereof comprising the step of administering to thesubject an effective amount of a CB1 inverse-agonist compound of thepresent invention in a combination product with one or morecontraceptives or composition thereof.

Appetite related syndromes, disorders or diseases include obesity,overweight condition, anorexia, bulimia, cachexia, dysregulated appetiteand the like.

Obesity related syndromes, disorders or diseases include obesity as aresult of genetics, diet, food intake volume, metabolic syndrome,disorder or disease, hypothalmic disorder or disease, age, reducedactivity, abnormal adipose mass distribution, abnormal adiposecompartment distribution and the like.

Metabolism related syndromes, disorders or diseases include metabolicsyndrome, dyslipidemia, elevated blood pressure, diabetes, insulinsensitivity or resistance, hyperinsulinemia, hypercholesterolemia,hyperlipidemias, hypertriglyceridemias, atherosclerosis, hepatomegaly,steatosis, abnormal alanine aminotransferase levels, inflammation,atherosclerosis and the like.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB1 antagonistcompound of the present invention or composition thereof The presentinvention includes a method for treating, ameliorating or preventing aCB1 receptor antagonist mediated syndrome, disorder or disease in asubject in need thereof comprising the step of administering to thesubject an effective amount of a CB1 antagonist compound of the presentinvention in a combination product with an anticonvulsant or compositionthereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB1 antagonistcompound of the present invention in a combination product with one ormore contraceptives or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB2 receptor agonist mediated syndrome, disorder or diseasein a subject in need thereof comprising the step of administering to thesubject an effective amount of a CB2 agonist compound of the presentinvention or composition thereof The present invention includes a methodfor treating, ameliorating or preventing a CB2 receptor agonist mediatedsyndrome, disorder or disease in a subject in need thereof comprisingthe step of administering to the subject an effective amount of a CB2agonist compound of the present invention in a combination product withan anticonvulsant or composition thereof.

The present invention includes include a method for treating,ameliorating or preventing a CB2 receptor inverse-agonist mediatedsyndrome, disorder or disease in a subject in need thereof comprisingthe step of administering to the subject an effective amount of a CB2inverse-agonist compound of the present invention or compositionthereof.

The present invention includes a method for treating, ameliorating orpreventing a CB2 receptor inverse-agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB2inverse-agonist compound of the present invention in a combinationproduct with an anticonvulsant or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB2 receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB2 antagonistcompound of the present invention or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB2 receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB2 antagonistcompound of the present invention in a combination product with ananticonvulsant or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a metabolism related syndrome, disorder or disease, anappetite related syndrome, disorder or disease, a diabetes relatedsyndrome, disorder or disease, an obesity related syndrome, disorder ordisease or a learning, cognition or memory related syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a compound of thepresent invention or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a metabolism related syndrome, disorder or disease, anappetite related syndrome, disorder or disease, a diabetes relatedsyndrome, disorder or disease, an obesity related syndrome, disorder ordisease or a learning, cognition or memory related syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a compound of thepresent invention in a combination product with an anticonvulsant orcomposition thereof.

The present invention includes a pharmaceutical composition ormedicament comprising an admixture of a compound of the presentinvention and an optional pharmaceutically acceptable carrier.

The present invention includes a pharmaceutical composition ormedicament comprising an admixture of two or more compounds of thepresent invention and an optional pharmaceutically acceptable carrier.

The present invention also includes a pharmaceutical composition ormedicament comprising an admixture of a compound of formula (I), ananticonvulsant and an optional pharmaceutically acceptable carrier.

Such pharmaceutical compositions are particularly useful for treating asubject suffering from a metabolism related syndrome, disorder ordisease, an appetite related syndrome, disorder or disease, a diabetesrelated syndrome, disorder or disease, an obesity related syndrome,disorder or disease, or a learning, cognition or memory relatedsyndrome, disorder or disease.

Anticonvulsants useful in the methods and compositions of the presentinvention in combination with a compound of formula (I) include, but arenot limited to, topiramate, analogs of topiramate, carbamazepine,valproic acid, lamotrigine, gabapentin, phenytoin and the like andmixtures or pharmaceutically acceptable salts thereof.

Topiramate, 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranosesulfamate, is currently marketed for the treatment of seizures inpatients with simple and complex partial epilepsy and seizures inpatients with primary or secondary generalized seizures in the UnitedStates, Europe and most other markets throughout the world. Topiramateis currently available for oral administration in round tabletscontaining 25 mg, 100 mg or 200 mg of active agent, and as 15 mg and 25mg sprinkle capsules for oral administration as whole capsules or openedand sprinkled onto soft food. U.S. Pat. No. 4,513,006, incorporatedherein by reference, discloses topiramate and analogs of topiramate,their manufacture and use for treating epilepsy. Additionally,topiramate may also be made by the process disclosed in U.S. Pat. Nos.5,242,942 and 5,384,327, which are incorporated by reference herein. Theterm “analogs of topiramate”, as used herein, refers to the sulfamatecompounds of formula (I), which are disclosed in U.S. Pat. No. 4,513,006(see, e.g., column 1, lines 36-65 of U.S. Pat. No. 4,513,006).

For use in the methods of the present invention in combination with acompound of the formula (I), topiramate (or an analog of topiramate) canbe administered in the range of about 10 to about 1000 mg daily,preferably in the range of about 10 to about 650 mg daily, morepreferably in the range of about 15 to about 325 mg once or twice daily.

Carbamazepine, 5H-dibenz[b,f]azepine-5-carboxamide, is an anticonvulsantand specific analgesic for trigeminal neuralgia, available for oraladministration as chewable tablets of 100 mg, tablets of 200 mg, XR(extended release) tablets of 100, 200, and 400 mg, and as a suspensionof 100 mg/5 mL (teaspoon); U.S. Pat. No. 2,948,718, herein incorporatedby reference in its entirety, discloses carbamazepine and its methods ofuse.

For use in the methods of the present invention in combination with acompound of the formula (I), carbamazepine can be administered in therange of about 200 to about 1200 mg/day; preferably, about 400 mg/day.

Valproic acid, 2-propylpentanoic acid or dipropylacetic acid, is anantiepileptic agent commercially available as soft elastic capsulescontaining 250 mg valproic acid, and as syrup containing the equivalentof 250 mg valproic acid per 5 mL as the sodium salt. Valproic acid andvarious pharmaceutically acceptable salts are disclosed in U.S. Pat. No.4,699,927, which is incorporated by reference herein in its entirety.

For use in the methods of the present invention in combination with acompound of the formula (I), valproic acid can be administered in therange of about 250 to about 2500 mg/day; preferably, about 1000 mg/day.

Lamotrigine, 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, is anantiepileptic drug commercially available for oral administration astablets containing 25 mg, 100 mg, 150 mg, and 200 mg of lamotrigine, andas chewable dispersible tablets containing 2 mg, 5 mg, or 25 mg oflamotrigine. Lamotrigine and its uses are disclosed in U.S. Pat. No.4,486,354, incorporated by reference herein in its entirety.

For use in the methods of the present invention in combination with acompound of the formula (I), lamotrigine can be administered in therange of about 50 to about 600 mg/day in one to two doses; preferably,about 200 to about 400 mg/day; most preferably, about 200 mg/day.

Gabapentin, 1-(aminomethyl)cyclohexaneacetic acid, is commerciallyavailable for the adjunctive treatment of epilepsy and for postherpeticneuralgia in adults as capsules containing 100 mg, 300 mg, and 400 mg ofgabapentin, film-coated tablets containing 600 mg and 800 mg ofgabapentin, and an oral solution containing 250 mg/5 mL of gabapentin.Gabapentin and its methods of use are described in U.S. Pat. Nos.4,024,175 and 4,087,544, herein incorporated by reference in theirentirety.

For use in the methods of the present invention in combination with acompound of the formula (I), gabapentin can be administered in the rangeof about 300 to about 3600 mg/day in two to three divided doses;preferably, about 300 to about 1800 mg/day; most preferably, about 900mg/day.

Phenytoin sodium, 5,5-diphenylhydantoin sodium salt, is ananticonvulsant, which is commercially available for oral administrationas capsules containing 100 mg, 200 mg or 300 mg of phenytoin sodium.

For use in the methods of the present invention in combination with acompound of the formula (I), phenytoin sodium can be administered in therange of about 100 to about 500 mg/day; preferably, about 300 to about400 mg/day; most preferably, about 300 mg/day.

The present invention also includes a pharmaceutical composition ormedicament comprising an admixture of a compound of formula (I), one ormore contraceptives and an optional pharmaceutically acceptable carrier.

Contraceptives suitable for use in a combination product include, forexample, ORTHO CYCLEN®, ORTHO TRI-CYCLEN®, ORTHO TRI-CYCLEN LO®, andORTHO EVRA®, all available from Ortho-McNeil Pharmaceutical, Inc.,Raritan, N.J. It should also be understood that contraceptives suitablefor use in the invention encompass those contraceptives that include afolic acid component.

Both smoking and obesity have been identified as risk factors in womentaking oral contraceptives. CB1 receptor antagonists and inverseagonists have been found to be useful therapeutic agents for reducingthe urge to smoke and for assisting patients with eating disorders tolose weight.

Accordingly, the invention further includes a method of reducing therisk factors associated with either smoking or obesity or both for womentaking contraceptives by co-administering with a contraceptive at leastone of a CB1 receptor antagonist of formula (I) or a CB1 receptorinverse-agonist compound of formula (I) or a mixture thereof.

The use of such compounds or a pharmaceutical composition or medicamentthereof is to either reduce the desire to smoke or assist in weight lossfor patients taking contraceptives or both.

Pharmaceutical Compositions

The term “composition” refers to a product comprising the specifiedingredients in the specified amounts, as well as any product thatresults, directly or indirectly, from combinations of the specifiedingredients in the specified amounts. The invention further comprisesmixing one or more of the compounds of the invention and apharmaceutically acceptable carrier; and, includes those compositionsresulting from such a process. Contemplated processes include bothtraditional and modern pharmaceutical techniques.

Pharmaceutical compositions of the invention may, alternatively or inaddition to a compound of formula (I), comprise a pharmaceuticallyacceptable salt of a compound of formula (I) or a prodrug orpharmaceutically active metabolite of such a compound or salt inadmixture with a pharmaceutically acceptable carrier.

The term “medicament” refers to a product for use in treating,ameliorating or preventing a cannabinoid receptor mediated syndrome,disorder or disease.

“Pharmaceutically acceptable carrier” means molecular entities andcompositions that are of sufficient purity and quality for use in theformulation of a composition of the invention and that, whenappropriately administered to an animal or a human, do not produce anadverse, allergic, or other untoward reaction.

Since both clinical and veterinary uses are equally included within thescope of the present invention, a pharmaceutically acceptableformulation would include a composition or medicament formulation foreither clinical or veterinary use.

The present invention includes a process for making the composition ormedicament comprising mixing any of the instant compounds and apharmaceutically acceptable carrier and include those compositions ormedicaments resulting from such a process. Contemplated processesinclude both conventional and unconventional pharmaceutical techniques.Other examples include a composition or medicament comprising a mixtureof at least two of the instant compounds in association with apharmaceutically acceptable carrier.

The composition or medicament may be administered in a wide variety ofdosage unit forms depending on the method of administration; whereinsuch methods include (without limitation) oral, sublingual, nasal(inhaled or insufflated), transdermal, rectal, vaginal, topical (with orwithout occlusion), intravenous (bolus or infusion) or for injection(intraperitoneally, subcutaneously, intramuscularly, intratumorally orparenterally) using a suitable dosage form well known to those ofordinary skill in the area of pharmaceutical administration.Accordingly, the term “dosage unit” or “dosage form” is alternativelyused to refer to (without limitation) a tablet, pill, capsule, solution,syrup, elixir, emulsion, suspension, suppository, powder, granule orsterile solution, emulsion or suspension (for injection from an ampouleor using a device such as an auto-injector or for use as an aerosol,spray or drop). Furthermore, the composition may be provided in a formsuitable for weekly or monthly administration (e.g. as an insoluble saltof the active compound (such as the decanoate salt) adapted to provide adepot preparation for intramuscular injection).

In preparing a dosage form, the principal active ingredient (such as acompound of the present invention or a pharmaceutically acceptable salt,racemate, enantiomer, or diastereomer thereof) is optionally mixed withone or more pharmaceutical carriers (such as a starch, sugar, diluent,granulating agent, lubricant, glidant, binder, disintegrating agent andthe like), one or more inert pharmaceutical excipients (such as water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents, syrup and the like), one or more conventional tabletingingredient (such as corn starch, lactose, sucrose, sorbitol, talc,stearic acid, magnesium stearate, dicalcium phosphate, any of a varietyof gums and the like) and a diluent (such as water and the like) to forma homogeneous composition (whereby the active ingredient is dispersed orsuspended evenly throughout the mixture) which may be readily subdividedinto dosage units containing equal amounts of a compound of the presentinvention.

Binders include, without limitation, starch, gelatin, natural sugars(such as glucose, beta-lactose and the like), corn sweeteners andnatural and synthetic gums (such as acacia, tragacanth, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and the like). Disintegrating agents include, withoutlimitation, starch, methyl cellulose, agar, bentonite, xanthan gum andthe like.

Because of the ease of administration, tablets and capsules represent anadvantageous oral dosage unit form, wherein solid pharmaceuticalcarriers are employed. If desired, tablets may be sugar or film coatedor enteric-coated by standard techniques. Tablets may also be coated orotherwise compounded to provide a prolonged therapeutic effect. Forexample, the dosage form may comprise an inner dosage and an outerdosage component, whereby the outer component is in the form of anenvelope over the inner component. The two components may further beseparated by a layer, which resists disintegration in the stomach (suchas an enteric layer) and permits the inner component to pass intact intothe duodenum or a layer which delays or sustains release. A variety ofenteric and nonenteric layer or coating materials may be used (such aspolymeric acids, shellacs, acetyl alcohol, cellulose acetate and thelike) or combinations thereof.

The liquid forms in which a compound of the present invention may beincorporated for oral administration include (without limitation),aqueous solutions, suitably flavored syrups, aqueous or oil suspensions(using a suitable synthetic or natural gum dispersing or suspendingagent such as tragacanth, acacia, alginate, dextran, sodiumcarboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone, gelatinand the like), flavored emulsions (using a suitable edible oil such ascottonseed oil, sesame oil, coconut oil, peanut oil and the like),elixirs and other similar liquid forms with a variety ofpharmaceutically acceptable vehicles.

As is also known in the art, the compounds may alternatively beadministered parenterally via injection. For parenteral administration,sterile solutions or injectable suspensions may be parenteral vehicleswherein appropriate liquid carriers, suspending agents and the like areemployed. Sterile solutions are a preferred parenteral vehicle. Isotonicpreparations that generally contain suitable preservatives are employedwhen intravenous administration is desired. A parenteral formulation mayconsist of the active ingredient dissolved in or mixed with anappropriate inert liquid carrier. Acceptable liquid carriers compriseaqueous solvents and the like and other optional ingredients for aidingsolubility or preservation. Such aqueous solvents include sterile water,Ringer's solution or an isotonic aqueous saline solution. Alternatively,a sterile non-volatile oil may be employed as a solvent agent. Otheroptional ingredients include vegetable oils (such as peanut oil,cottonseed oil, sesame oil and the like), organic solvents (such assolketal, glycerol, formyl and the like), preservatives, isotonizers,solubilizers, stabilizers, pain-soothing agents and the like. Aparenteral formulation is prepared by dissolving or suspending theactive ingredient in the liquid carrier whereby the final dosage unitcontains from 0.005 to 10% by weight of the active ingredient.

Compounds of the present invention may be administered intranasallyusing a suitable intranasal vehicle. Compounds of the present inventionmay be administered topically using a suitable topical transdermalvehicle or a transdermal patch. Administration via a transdermaldelivery system requires a continuous rather than intermittent dosageregimen.

Compounds of the present invention may also be administered via a rapiddissolving or a slow release composition, wherein the compositionincludes a biodegradable rapid dissolving or slow release carrier (suchas a polymer carrier and the like) and a compound of the invention.Rapid dissolving or slow release carriers are well known in the art andare used to form complexes that capture therein an active compound(s)and either rapidly or slowly degrade/dissolve in a suitable environment(e.g., aqueous, acidic, basic, etc). Such particles are useful becausethey degrade/dissolve in body fluids and release the active compound(s)therein. The particle size of a compound of the present invention,carrier or any excipient used in such a composition may be optimallyadjusted using techniques known to those of ordinary skill in the art.

The present invention includes a composition of an instant compound orprodrug thereof present in a prophylactically or therapeuticallyeffective amount necessary for symptomatic relief to a subject in needthereof A prophylactically or therapeutically effective amount of aninstant compound or prodrug thereof may range from about 0.01 ng toabout 1 g and may be constituted into any form suitable for theadministration method and regimen selected for the subject.

Depending on the subject and disease to be treated, the prophylacticallyor therapeutically effective amount for a person of average body weightof about 70 kg per day may range from about 0.0 1 ng/kg to about 300mg/kg; from about 0.1 ng/kg to about 200 mg/kg; from about 0.5 ng/kg toabout 100 mg/kg; or, from about 0.1 ng/kg to about 50 mg/kg.

An optimal prophylactically or therapeutically effective amount andadministration method and regimen may be readily determined by thoseskilled in the art, and will vary depending on factors associated withthe particular patient being treated (age, weight, diet and time ofadministration), the severity of the condition being treated, thecompound and dosage unit being employed, the mode of administration andthe strength of the preparation.

Dosage unit(s) may be administered to achieve the therapeutically orprophylactically effective amount in a regimen of from about once perday to about 5 times per day. The preferred dosage unit for oraladministration is a tablet containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5,5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 or 500 mg of the activeingredient.

Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic schemes described below and areillustrated more particularly in the specific synthetic examples thatfollow. The general schemes and specific examples are offered by way ofillustration; the invention should not be construed as being limited bythe chemical reactions and conditions expressed. The methods forpreparing the various starting materials used in the schemes andexamples are well within the skill of persons versed in the art. Noattempt has been made to optimize the yields obtained in any of theexample reactions. One skilled in the art would know how to increasesuch yields through routine variations in reaction times, temperatures,solvents or reagents.

The terms used in describing the invention are commonly used and knownto those skilled in the art. When used herein, the followingabbreviations and formulae have the indicated meanings:

Abbreviation Meaning Cpd compound (Boc)₂O di-tert-butyldicarbonate EtOAcethyl acetate Et₂O anhydrous ether K₂CO₃ potassium carbonate KOtBupotassium tert-butoxide LHMDS or LiHMDS lithium bis(trimethylsilyl)amidemin(s)/hr(s) minute(s)/hour(s) RT/rt/r.t. room temperature SOCl₂ thionylchloride TEA or Et₃N triethylamine TFA trifluoroacetic acid THFtetrahydrofuran

Compound A1 in a reagent solution (such as aqueous KOH and the like) isreacted with a solution of Compound A2 to yield a Compound A3. Asolution of Compound A3 (in a solvent such as Et₂O, THF and the like ora mixture thereof) in a reagent solution (such as LHMDS and the like ina solvent such as Et₂O or THF and the like or a mixture thereof) isreacted with a solution of oxalic acid diethyl ester Compound A4 (in asolvent such as Et₂O, THF and the like or a mixture thereof) to yield aCompound A5.

The oxalic acid diethyl ester Compound A4 is used by way of illustrationin this scheme; the scope of compounds representative of the presentinvention should not be construed as being limited to the use of oxalicacid diethyl ester or by the unsubstituted diethyl ester portions ofCompound A4. The present invention includes compounds prepared usingother esters such as dimethoxy-acetic acid methyl ester and the like oresters which are further substituted in place of Compound A4 usingtechniques known to those skilled in the art.

A solution of Compound A5 (in a solvent such as one or more of MeOH,EtOH, CH₂Cl₂ and the like) is reacted with a substituted mono ordihydrochloride phenyl hydrazine Compound A6 to provide a Compound A7.

The monohydrochloride or dihydrochloride hydrazine Compound A6 may beconverted to the free base by methods known to those skilled in the art.In the examples of the present invention, the free base is preparedeither in situ (as shown for illustrative purposes in this Scheme) orseparately (then added to the reaction mixture) by reaction with K₂CO₃.As illustrated in this Scheme, Compound A6 may also be furthersubstituted with a variety of R₂ substituents (as defined herein). Inmany instances, the substituted hydrazine Compound A6 is commerciallyavailable. When not commercially available, a particularly substitutedCompound A6 may be prepared by methods known to those skilled in theart.

Compound A7 is reacted in a reagent solution (such as LiOH or NaOH in asolvent such as a mixture of THF, ethanol and water and the like) toprovide a Compound A8.

Compound A8 is reacted in a reagent solution (such as SOCl₂ and the likein a solvent such as CH₂Cl₂ and the like) at reflux temperature toprovide a Compound A9. A solution of Compound A9 (in a suitable solvent)is reacted with a solution of a Compound A10 (in a suitable solvent) toprovide a Compound of formula (I).

The synthetic examples that follow herein describe more completely thepreparation of particular compounds included within the scope of thepresent invention.

EXAMPLE 15-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R)-1-cyclohexyl-ethyl]-amide (Cpd 8)

To p-chlorobenzaldehyde Compound la (1.4 g, 10 mmol) was added aqueousKOH (0.25 g in 4.4 mL water). The mixture was heated to 65° C. PentanoneCompound A2 (1.1 mL, 10 mmol) was added dropwise over 10 minutes, andthe reaction mixture was refluxed for 5 h before being cooled to roomtemperature and stirred at room temperature overnight. The reactionmixture was acidified with 1N HCl (26 mL) and diluted with EtOAc. Theorganic layer was separated, washed with brine, dried over sodiumsulfate and evaporated to give the crude product. The crude was thenpurified on silica gel column with 5% EtOAc/Hexane to give 0.65 g (31%)of the desired product 1-(4-chloro-phenyl)-2-methyl-pent-1-en-3-oneCompound 1b.

To a solution of lithium bis(trimethylsilyl)amide (LHMDS) (3.125 mL of1.0 M solution in THF) in 10 mL THF at −78° C. was added Compound 1b(0.65 g, 3.125 mmol) in 2 mL THF dropwise. The mixture was stirred at−78° C. for 1 h. Oxalic acid diethyl ester Compound A4 (0.46 g, 3.125mmol) in 2 mL THF was added slowly at −78° C. The mixture was stirred atthe same temperature for 1 hr, then allowed to gradually warm to roomtemperature and was stirred at room temperature overnight. The mixturewas concentrated and taken up in 100 mL EtOAc and washed with 1N HCl(2×50 mL), H₂O (2×50 mL). The organic layer was dried over sodiumsulfate and evaporated to give6-(4-chloro-phenyl)-3,5-dimethyl-2,4-dioxo-hex-5-enoic acid ethyl esterCompound 1c (0.6 g, 62%) as an orange oil, which was used in the nextstep without further purification.

Compound 1c (0.6 g, 1.94 mmol) was taken up in ethanol (20 mL). To thiswas added anhydrous 2,4-dichlorophenylhydrazine Compound 1d (0.34 g,1.94 mmol) and K₂CO₃ (0.54 g, 1.94 mmol). The resulting mixture wasstirred at room temperature overnight before being filtered and washedwith ethanol (20 mL). The combined filtrate was concentrated andpurified on silica gel column with 20% EtOAc/Hexane to give 0.26 g (30%)of5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid ethyl ester Compound 1e.

Compound 1e (0.26 g, 0.58 mmol) was dissolved in THF (6 mL). Aqueouslithium hydroxide (LiOH) (0.071 g in 2 mL) was added followed by ethanol(1 mL). The mixture was stirred at room temperature for 48 h, thenconcentrated, diluted with water (10 mL) and acidified to pH 4 using 1NHCl. The aqueous suspension was extracted with EtOAc (50 mL). Theorganic layer was washed with brine, dried over magnesium sulfate andevaporated to give5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid Compound 1f (0.23 g, 96%).

Compound 1f (0.23 g, 0.55 mmol) was taken up in CH₂Cl₂ (4 mL) andtreated with thionyl chloride (0.33 mL). The resulting solution washeated to reflux for 3 h and the solvent was removed in vacuo to obtain5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carbonylchloride Compound 1g (0.24 g, 99%).

To a solution of (1R)-1-cyclohexyl-ethylamine Compound 1h (0.02 g, 0.15mmol) in CH₂Cl₂ (2 mL) and Et₃N (0.04 mL, 0.45 mmol) was added asolution of Compound 1i (0.044 g, 0.1 mmol). The resulting suspensionwas stirred at room temperature for 2 h and then diluted with CH₂Cl₂ (10mL). The resulting mixture was washed with 1N HCl (2×10 mL) and H₂O(2×10 mL). The organic layer was dried over sodium sulfate, thenconcentrated and purified on silica gel column with 10% EtOAc/Hexane togive the title Compound 8 (40 mg, 75%). MS 530 (MH⁺).

Following the procedure of Example 1, substituting the appropriatestarting materials, reagents and solvents, the following compounds wereprepared:

Cpd Name MS (MH⁺) 15-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 530phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-cyclohexyl-ethyl]-amide 25-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 524phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-phenyl-ethyl]-amide 35-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 556phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R,2S,4R)-1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl]-amide 45-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 503phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide 55-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 505phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid morpholin-4- ylamide 65-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 502phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid cyclohexylamide 75-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 516phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (2-methyl-cyclohexyl)-amide 95-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 516phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid cyclohexylmethyl-amide 105-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 496phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid phenylamide 115-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 524phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide 125-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 503phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1- ylamide 135-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 505phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid morpholin-4- ylamide 141-{[5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 518phenyl)-4-methyl-1H-pyrazole-3-carbonyl]-amino}-1-methyl- piperidinium15 {[5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 554phenyl)-4-methyl-1H-pyrazole-3-carbonyl]-amino}-phenyl- acetic acid 165-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 530phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-cyclohexyl-ethyl]-amide 175-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 524phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-phenyl-ethyl]-amide 185-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 530phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-cyclohexyl-ethyl]-amide 195-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 524phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide 205-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 511phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (2-amino- phenyl)-amide21 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)- 4984-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-cyclohexyl- ethyl]-amide22 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)- 4924-methyl-1H-pyrazole-3-carboxylic acid [(1S)-1-phenyl-ethyl]- amide 235-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)- 4924-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]- amide 245-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)- 4984-methyl-1H-pyrazole-3-carboxylic acid [(1R)-1-cyclohexyl- ethyl]-amide25 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)- 4714-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide 265-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)- 4734-methyl-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 275-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 434phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid methylamide 285-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 476phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(R)-sec- butyl]-amide 295-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro- 476phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [(S)-sec- butyl]-amide

Additional compounds may be made according to the synthetic methods ofthe present invention by one skilled in the art, differing only inpossible starting materials, reagents and conditions used in the instantmethods.

BIOLOGICAL EXAMPLES

The following examples illustrate that the compounds of the presentinvention are CB receptor modulators useful for treating, amelioratingor preventing a cannabinoid receptor mediated syndrome, disorder ordisease in a subject in need thereof.

EXAMPLE 1 Binding Assay for CB1 or CB2 Agonists or Inverse Agonists

The human CB1 and CB2 receptors were stably expressed in SK-N-MC cellstransfected with pcDNA3 CB-1 (human) or pcDNA3 CB-2 (human). The cellswere grown in T-180 cell culture flasks under standard cell cultureconditions at 37° C. in a 5% CO₂ atmosphere. The cells were harvested bytrysinization and homogenized in a homogenization buffer (10 mM Tris,0.2 mM MgCl₂, 5 mM KCl, with protease inhibitors aprotinin, leupeptin,pepstatin A and bacitracin) and centrifuged (2000 g). The supernatantwas then centrifuged in 2M sucrose (31,300 g) to produce a semi-purifiedmembrane pellet. The pellet was resuspended in homogenization and storedat −80° C.

On the day of the assay, the pellet was thawed on ice and diluted inassay buffer (50 mM Tris-HCl, 5 mM MgCl₂, 2.5 mM EDTA, 0.5 mg/mL fattyacid free bovine serum albumin, pH 7.5). The diluted membrane pellet wasadded with buffer, either a test compound or vehicle standard and theradioligand [H]³⁺-CP-55,940 (0.2 nM) to the wells of a 96-wellpolypropylene plate. Non-specific binding was measured in wellscontaining WIN 55,212 (10 uM). The plate was covered and incubated for90 minutes at 30° C. The contents were then aspirated onto a PackardUnifilter GF/C filter bottom plate prewet with 0.5% polyethyleneimine.The wells of the polypropylene plate were rinsed and aspirated seventimes with a 0.9% saline-0.5% Tween 20 solution. The Unifilter plate wasdried, scintillation cocktail was added to each well and the countsrepresenting binding were quantitated in a TopCount scintillationcounter.

CB1 and CB2 Receptor Binding Results

For compounds tested, an IC₅₀ binding value was obtained from percentinhibition studies in which various test concentrations were used. Thebinding value was calculated by linear regression.

For compounds without an IC₅₀ binding value, the percent inhibition (%)was obtained at a test concentration of ^(a)1.0 μM or ^(b)0.2 μM.

TABLE 1 Cannabinoid CB1 Receptor Binding Cpd Binding 1 0.02 2 0.02 30.05 4 0.09 5 0.36 6 0.13 7 0.11 8 0.31 9 0.37 10 0.6  11 0.34 12 0.2513 ^(a)53% 16 0.33 17 0.25 18 0.09 19 0.37 21 0.13 23 0.3  24 0.28 27^(b)11% 28 0.07 29 ^(b)52%

TABLE 2 Cannabinoid CB2 Receptor Binding Cpd Binding 1 ^(a)42% 2 ^(a)32%3 ^(a)31% 4 1.7 5 2   6 ^(a)40% 7 ^(a)55% 8 ^(a)39% 9 ^(a)49% 10 ^(a)46%11 ^(a)51% 27 ^(b)18% 28 ^(b)21% 29  ^(b)9%

EXAMPLE 2 Functional Cell-Based Assay for CB1 or CB2 Agonist and InverseAgonist Effects on Intra-Cellular Adenylate Cyclase Activity

The CB1 and CB2 receptors are G-protein coupled receptors (GPCR), whichinfluence cell function via the Gi-protein. These receptors modulate theactivity of intracellular adenylate cyclase, which in turn produces theintracellular signal messenger cyclic-AMP (cAMP).

At baseline, or during non-ligand bound conditions, these receptors areconstitutively active and tonically suppress adenylate cyclase activity.The binding of an agonist causes further receptor activation andproduces additional suppression of adenylate cyclase activity. Thebinding of an inverse agonist inhibits the constitutive activity of thereceptors and results in an increase in adenylate cyclase activity.

By monitoring intracellular adenylate cyclase activity, the ability ofcompounds to act as agonists or inverse agonists can be determined.

Assay

Test compounds are evaluated in SK-N-MC cells which, using standardtransfection procedures, are stably transfected with human cDNA forpcDNA3-CRE β-gal and pcDNA3 CB1 receptor (human) or pcDNA3 CB2 receptor(human). By expressing CRE β-gal, the cells produce β-galactosidase inresponse to CRE promoter activation by cAMP. Cells expressing CRE β-galand either the human CB1 or CB2 receptor will produce lessβ-galactosidase when treated with a CB1/CB2 agonist and will producemore β-galactosidase when treated with a CB1/CB2 inverse agonist.

Cell Growth

The cells are grown in 96-well plates under standard cell cultureconditions at 37° C. in a 5% CO₂ atmosphere. After 3 days, the media isremoved and a test compound in media (wherein the media is supplementedwith 2 mM L-glutamine, 1M sodium pyruvate, 0.1% low fatty acid FBS(fetal bovine serum) and antibiotics) is added to the cell. The platesare incubated for 30 minutes at 37° C. and the plate cells are thentreated with forskolin over a 4-6 hour period, then washed and lysed.The β-galactosidase activity is quantitated using commercially availablekit reagents (Promega Corp. Madison, Wis.) and a Vmax Plate Reader(Molecular Devices, Inc).

CB1 Receptor Mediated Change in CRE β-gal Expression

For cells expressing CRE β-gal and the CB1 receptor, CB1 agonists reduceβ-galactosidase activity in a dose-dependent manner and CB1 inverseagonists increase β-galactosidase activity in a dose-dependent manner.

The change in β-galactosidase activity is determined by setting avehicle treated cell's activity value at 100% and expressing theβ-galactosidase activity measured in a corresponding compound treatedcell as a percent of the vehicle treated cell activity.

CB2 Receptor Mediated Change in CRE β-gal Expression

For cells expressing CRE β-gal and the CB2 receptor, CB2 agonists reduceβ-galactosidase activity in a dose-dependent manner and CB2 inverseagonists increase β-galactosidase activity in a dose-dependent manner.

The change in β-galactosidase activity is determined by setting avehicle treated cell's activity value at 100% and expressing theβ-galactosidase activity measured in a corresponding compound treatedcell as a percent of the vehicle treated cell activity.

It is to be understood that the preceding description of the inventionand various examples thereof have emphasized certain aspects. Numerousother equivalents not specifically elaborated on or discussed maynevertheless fall within the spirit and scope of the present inventionor the following claims and are intended to be included.

1. A compound having a structure according to formula (I):

or a form thereof, wherein R_(1a) is hydrogen or alkyl; R_(1b) isselected from C₃₋₁₂cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl,wherein alkyl is optionally substituted with carboxy, C₃₋₁₂cycloalkyl,heterocyclyl, aryl or heteroaryl, wherein each instance ofC₃₋₁₂cycloalkyl, heterocyclyl, aryl or heteroaryl is optionallysubstituted with one, two, three or four substituents selected fromalkyl, alkoxy, cyano, halogen, hydroxy, amino or alkylamino, and whereinheterocyclyl optionally has one nitrogen ring atom attached to theformula (I) nitrogen atom, wherein said nitrogen ring atom is optionallyfurther substituted with alkyl to form a quaternary ammonium salt;alternatively, R_(1a) and R_(1b) are taken together with the nitrogenatom of attachment to form a ring selected from piperidinyl orpiperazinyl; and, R₂ and R₃ are each selected from one or two alkyl,alkoxy, cyano or halogen substituents.
 2. The compound of claim 1,wherein R_(1a) is hydrogen.
 3. The compound of claim 1, wherein R_(1b)is selected from C₃₋₁₂cycloalkyl, heterocyclyl, aryl or alkyl, whereinalkyl is optionally substituted with carboxy, C₃₋₁₂cycloalkyl or aryl,wherein each instance of C₃₋₁₂cycloalkyl or aryl is optionallysubstituted with one, two, three or four substituents selected fromalkyl, alkoxy, cyano, halogen, hydroxy, amino or alkylamino.
 4. Thecompound of claim 1, wherein R_(1b) is selected from C₃₋₁₂cycloalkyl,heterocyclyl, aryl or alkyl, wherein alkyl is optionally substitutedwith C₃₋₁₂cycloalkyl or aryl, wherein each instance of C₃₋₁₂cycloalkylis optionally substituted with one, two or three alkyl substituents, andwherein each instance of aryl is optionally substituted with an amino oralkylamino substituent.
 5. The compound of claim 1, wherein R_(1b) isselected from cyclohexyl, bicyclo[2.2.1]heptyl, piperidinyl,morpholinyl, phenyl or alkyl, wherein alkyl is optionally substitutedwith carboxy, cyclohexyl or phenyl, wherein each instance of cyclohexylor bicyclo[2.2.1]heptyl is optionally substituted with one, two or threemethyl or ethyl substituents, and wherein each instance of phenyl isoptionally substituted with an amino or alkylamino substituent.
 6. Thecompound of claim 1, wherein R_(1b) is selected from C₃₋₁₂cycloalkyl,heterocyclyl or alkyl, wherein alkyl is optionally substituted withC₃₋₁₂cycloalkyl or aryl, wherein C₃₋₁₂cycloalkyl is optionallysubstituted with three alkyl substituents.
 7. The compound of claim 1,wherein R_(1b) is selected from bicyclo[2.2.1]heptyl, piperidinyl oralkyl, wherein alkyl is optionally substituted with cyclohexyl orphenyl, wherein bicyclo[2.2.1]heptyl is optionally substituted withthree alkyl substituents.
 8. The compound of claim 1, wherein R_(1b) ispiperidinyl having one nitrogen ring atom attached to the formula (I)nitrogen atom, wherein said nitrogen ring atom is optionally furthersubstituted with methyl to form a quaternary piperidinium salt.
 9. Thecompound of claim 1, wherein R₂ and R₃ are one or two substituentsselected from fluoro or chloro.
 10. The compound of claim 1, wherein R₂is two substituents selected from fluoro or chloro.
 11. The compound ofclaim 1, wherein R₂ is two chloro substituents.
 12. The compound ofclaim 1, wherein R₃ is one chloro substituent.
 13. The compound of claim1, wherein R_(1a) is hydrogen; R_(1b) is selected from cyclohexyl,bicyclo[2.2.1]heptyl, piperidinyl, morpholinyl, phenyl or alkyl, whereinalkyl is optionally substituted with carboxy, cyclohexyl or phenyl,wherein each instance of cyclohexyl or bicyclo[2.2.1]heptyl isoptionally substituted with one, two or three methyl or ethylsubstituents, and wherein each instance of phenyl is optionallysubstituted with an amino or alkylamino substituent, or R_(1b) ispiperidinyl having one nitrogen ring atom attached to the formula (I)nitrogen atom, wherein said nitrogen ring atom is optionally furthersubstituted with methyl to form a quaternary piperidinium salt; R₂ istwo substituents selected from fluoro or chloro; and R₃ is one chlorosubstituent.
 14. A compound or a form thereof selected from the groupconsisting of:5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1S)-1-cyclohexyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1S)-1-phenyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R,2S,4R)-1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid piperidin-1-ylamide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid morpholin-4-ylamide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid cyclohexylamide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid (2-methyl-cyclohexyl)-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R)-1-cyclohexyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid cyclohexylmethyl-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid phenylamide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid piperidin-1-ylamide,5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid morpholin-4-ylamide,1-{[5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carbonyl]-amino}-1-methyl-piperidinium,{[5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carbonyl]-amino}-phenyl-aceticacid,5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1S)-1-cyclohexyl-ethyl]-amide,5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1S)-1-phenyl-ethyl]-amide,5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R)-1-cyclohexyl-ethyl]-amide,5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid (2-amino-phenyl)-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1S)-1-cyclohexyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1S)-1-phenyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R)-1-cyclohexyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid piperidin-1-ylamide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid morpholin-4-ylamide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid methylamide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(R)-sec-butyl]-amide, and5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(S)-sec-butyl]-amide.
 15. The compound of claim 14, wherein thecompound or form thereof is selected from the group consisting of:5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1S)-1-cyclohexyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1S)-1-phenyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R,2S,4R)-1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid piperidin-1-ylamide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid morpholin-4-ylamide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid cyclohexylamide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid (2-methyl-cyclohexyl)-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R)-1-cyclohexyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid cyclohexylmethyl-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid phenylamide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid piperidin-1-ylamide,5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid morpholin-4-ylamide,5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1S)-1-cyclohexyl-ethyl]-amide,5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1S)-1-phenyl-ethyl]-amide,5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R)-1-cyclohexyl-ethyl]-amide,5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1 S)-1-cyclohexyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-difluoro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R)-1-cyclohexyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(R)-sec-butyl]-amide, and5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(S)-sec-butyl]-amide.
 16. The compound of claim 15, wherein thecompound or form thereof is selected from the group consisting of:5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1S)-1-cyclohexyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1S)-1-phenyl-ethyl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R,2S,4R)-1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl]-amide,5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid piperidin-1-ylamide,5-[2-(3-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(1R)-1-cyclohexyl-ethyl]-amide, and5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid [(R)-sec-butyl]-amide.
 17. The compound of claim 1, wherein thecompound is an isolated form thereof.
 18. The compound of claim 1,wherein the compound is a cannabinoid receptor modulator, wherein thecannabinoid receptor is a CB1 or CB2 receptor, and wherein the modulatorcompound is an agonist, antagonist or inverse-agonist of the receptor.19. A composition comprising an effective amount of a compound of claim1 and a pharmaceutically acceptable carrier.
 20. The composition ofclaim 19, wherein the effective amount is in a range of from about 0.001mg/kg to about 300 mg/kg of body weight per day.
 21. A process forpreparing a composition comprising the step of admixing a compound ofclaim 1 and a pharmaceutically acceptable carrier.
 22. A medicamentcomprising an effective amount of a compound of claim
 1. 23. A methodfor using the compound of claim 1 for modulating cannabinoid receptoractivity comprising contacting the receptor with the compound.
 24. Amethod for treating, ameliorating or preventing a cannabinoid receptormediated syndrome, disorder or disease in a subject in need thereofcomprising the step of administering to the subject an effective amountof the compound of claim
 1. 25. The method of claim 24, wherein thesyndrome, disorder or disease is related to appetite, metabolism,diabetes, glaucoma-associated intraocular pressure, social and mooddisorders, seizures, substance abuse, learning, cognition or memory,organ contraction or muscle spasm, bowel disorders, respiratorydisorders, locomotor activity or movement disorders, immune andinflammation disorders, unregulated cell growth, pain management orneuroprotection.
 26. The method of claim 24, wherein the effectiveamount of the compound is from about 0.001 mg/kg/day to about 300mg/kg/day.
 27. The method of claim 24, further comprising treating,ameliorating or preventing a CB1 receptor inverse-agonist mediatedappetite related, obesity related or metabolism related syndrome,disorder or disease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of the compound,wherein the compound is an inverse-agonist of the receptor.
 28. Themethod of claim 24, wherein the effective amount of the compound is fromabout 0.001 mg/kg/day to about 300 mg/kg/day.
 29. The method of claim24, further comprising the step of administering to the subject acombination product comprising an effective amount of the compound and atherapeutic agent, wherein the therapeutic agent is an anticonvulsant ora contraceptive agent.
 30. The method of claim 29, wherein theanticonvulsant is topiramate, analogs of topiramate, carbamazepine,valproic acid, lamotrigine, gabapentin, phenytoin and the like andmixtures or pharmaceutically acceptable salts thereof.
 31. The method ofclaim 29, wherein the contraceptive agent is a progestin-onlycontraceptive, a contraceptive having a progestin component and anestrogen component, or an oral contraceptive optionally having a folicacid component.
 32. A method of contraception in a subject comprisingthe step of administering to the subject a composition, wherein thecomposition comprises a contraceptive and the compound of claim 1,wherein the composition reduces the urge to smoke in the subject orassists the subject in losing weight or both, and wherein the compoundof claim 1 is a CB1 receptor inverse-agonist or antagonist.
 33. A use ofthe compound of claim 1 in the manufacture of a medicament for treating,ameliorating or preventing a CB receptor mediated syndrome, disorder ordisease.
 34. The use of claim 33, wherein the syndrome, disorder ordisease is related to appetite, metabolism, diabetes,glaucoma-associated intraocular pressure, social and mood disorders,seizures, substance abuse, learning, cognition or memory, organcontraction or muscle spasm, bowel disorders, respiratory disorders,locomotor activity or movement disorders, immune and inflammationdisorders, unregulated cell growth, pain management or neuroprotection.